ABSTRACT
Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of Citrus (Rutaceae). Considering previous reports demonstrating that NTK inhibited inflammatory signaling pathways, this study aimed to investigate the effects of this compound in mice models of acute and chronic inflammation. Murine models of paw edema induced by carrageenan, dextran, histamine, and arachidonic acid, as well as carrageenan-induced peritonitis and pleurisy, were used to evaluate the effects of NTK on acute inflammation. A murine model of granuloma induced by cotton pellets was used to access the impact of NTK treatment on chronic inflammation. In the acute inflammation models, NTK demonstrated antiedematogenic effects and inhibited leukocyte recruitment, which was associated with decreased vascular permeability, inhibition of myeloperoxidase (MPO), interleukin (IL)1-ß, and tumor necrosis factor (TNF)-α production. In silico analysis suggest that NTZ anti-inflammatory effects may also occur due to inhibition of cyclooxygenase (COX)-2 activity and antagonism of the histamine receptor type 1 (H1). These mechanisms might have contributed to the reduction of granuloma weight and protein concentration in the homogenates, observed in the chronic inflammation model. In conclusion, NTK exerted anti-inflammatory effects that are associated with inhibition of IL1-ß and TNF-α production, possibly due to inhibition of COX-2 activity and antagonism of the H1 receptor. However, further studies are required to characterize the effects of this compound on chronic inflammation.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Edema/drug therapy , Granuloma/drug therapy , Inflammation/drug therapy , Polycyclic Sesquiterpenes/pharmacology , Acute-Phase Reaction/drug therapy , Acute-Phase Reaction/metabolism , Animals , Anti-Inflammatory Agents/administration & dosage , Capillary Permeability/drug effects , Carrageenan/toxicity , Cotton Fiber/toxicity , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Disease Models, Animal , Edema/chemically induced , Female , Granuloma/chemically induced , Histamine/chemistry , Inflammation/metabolism , Interleukin-1beta/metabolism , Leukocytes/drug effects , Leukocytes/immunology , Male , Mice , Molecular Docking Simulation , Peritonitis/drug therapy , Peritonitis/metabolism , Peroxidase/antagonists & inhibitors , Peroxidase/metabolism , Pleurisy/drug therapy , Pleurisy/metabolism , Polycyclic Sesquiterpenes/administration & dosage , Receptors, Histamine/chemistry , Receptors, Histamine/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Histamine is an important biogenic amine, which acts with a group of four G-protein coupled receptors (GPCRs), namely H(1) to H(4) (H(1)R - H(4)R) receptors. The actions of histamine at H(4)R are related to immunological and inflammatory processes, particularly in pathophysiology of asthma, and H(4)R ligands having antagonistic properties could be helpful as antiinflammatory agents. In this work, molecular modeling and QSAR studies of a set of 30 compounds, indole and benzimidazole derivatives, as H(4)R antagonists were performed. The QSAR models were built and optimized using a genetic algorithm function and partial least squares regression (WOLF 5.5 program). The best QSAR model constructed with training set (N = 25) presented the following statistical measures: r (2) = 0.76, q (2) = 0.62, LOF = 0.15, and LSE = 0.07, and was validated using the LNO and y-randomization techniques. Four of five compounds of test set were well predicted by the selected QSAR model, which presented an external prediction power of 80%. These findings can be quite useful to aid the designing of new anti-H(4) compounds with improved biological response.